• Journal of the Korean Society of Radiology
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• v.8 no.7
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• pp.389-395
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• 2014

The research was carried out to develop a animal model of malignant brain tumor for the researches in glioblastoma multiform (GBM) diagnosis and therapy. C6 cells were transplanted into the right striatum of SD rat using stereotactic instrument for the development. The developed animal model was verified by MRI and H&E stain assay of anatomicohistological examination. The MRI observations showed that the tumor developed at the injection site at the 7 days after glioblastoma inoculation. At 14 days post inoculation, the tumor grew to a large volume occupying almost a half of the right cerebral hemisphere. It was confirmed that the expression of excessive mitosis and pleomorphism in anatomicohistological examination. The developed animal model must be necessary and useful tool for the in vivo level research in the development of the new modality for the diagnosis and therapy of brain cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7811-7816
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• 2014

Background: Despite advances in radiotherapy, overall survival of glioblastoma multiforme (GBM) patients is still poor. Moreover dosimetrical analyses with these newer treatment methods are insufficient. The current study is aimed to compare intensity modulated radiation therapy (IMRT) linear accelerator (linac) and helical tomotherapy (HT) treatment plans for patients with prognostic aggressive brain tumors. Material and Methods: A total of 20 GBM patient plans were prospectively evaluated in both linac and HT planning systems. Plans are compared with respect to homogenity index, conformity index and organs at risk (OAR) sparing effects of the treatments. Results: Both treatment plans provided good results that can be applied to GBM patients but it was concluded that if the critical organs with relatively lower dose constraints are closer to the target region, HT for radiotherapeutical application could be preferred. Conclusion: Tomotherapy plans were superior to linear accelerator plans from the aspect of OAR sparing with slightly broader low dose ranges over the healthy tissues. In case a clinic has both of these IMRT systems, employment of HT is recommended based on the observed results and future re-irradiation strategies must be considered.

• Radiation Oncology Journal
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• v.37 no.1
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• pp.13-21
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• 2019

Purpose: Glioblastoma (GBM) carries a high propensity for in-field failure despite trimodality management. Past studies have failed to show outcome improvements with dose-escalation. Herein, we examined trends and outcomes associated with dose-escalation for GBM. Materials and Methods: The National Cancer Database was queried for GBM patients who underwent surgical resection and external-beam radiation with chemotherapy. Patients were excluded if doses were less than 59.4 Gy; dose-escalation referred to doses ≥66 Gy. Odds ratios identified predictors of dose-escalation. Univariable and multivariable Cox regressions determined potential predictors of overall survival (OS). Propensity-adjusted multivariable analysis better accounted for indication biases. Results: Of 33,991 patients, 1,223 patients received dose-escalation. Median dose in the escalation group was 70 Gy (range, 66 to 89.4 Gy). The use of dose-escalation decreased from 8% in 2004 to 2% in 2014. Predictors of escalated dose were African American race, lower comorbidity score, treatment at community centers, decreased income, and more remote treatment year. Median OS was 16.2 months and 15.8 months for the standard and dose-escalated cohorts, respectively (p = 0.35). On multivariable analysis, age >60 years, higher comorbidity score, treatment at community centers, decreased education, lower income, government insurance, Caucasian race, male gender, and more remote year of treatment predicted for worse OS. On propensity-adjusted multivariable analysis, age >60 years, distance from center >12 miles, decreased education, government insurance, and male gender predicted for worse outcome. Conclusion: Dose-escalated radiotherapy for GBM has decreased over time across the United States, in concordance with guidelines and the available evidence. Similarly, this large study did not discern survival improvements with dose-escalation.

• Investigative Magnetic Resonance Imaging
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• v.21 no.1
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• pp.9-19
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• 2017

Background: Normalized cerebral blood volume (nCBV) can be measured using manual or semiautomatic segmentation method. However, the difference in diagnostic performance on brain tumor differentiation between differently measured nCBV has not been evaluated. Purpose: To compare the diagnostic performance of manually obtained nCBV to that of semiautomatically obtained nCBV on glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) differentiation. Materials and Methods: Histopathologically confirmed forty GBM and eleven PCNSL patients underwent 3T MR imaging with dynamic susceptibility contrast-enhanced perfusion MR imaging before any treatment or biopsy. Based on the contrast-enhanced T1-weighted imaging, the mean nCBV (mCBV) was measured using the manual method (manual mCBV), random regions of interest (ROIs) placement by the observer, or the semiautomatic segmentation method (semiautomatic mCBV). The volume of enhancing portion of the tumor was also measured during semiautomatic segmentation process. T-test, ROC curve analysis, Fisher's exact test and multivariate regression analysis were performed to compare the value and evaluate the diagnostic performance of each parameter. Results: GBM showed a higher enhancing volume (P = 0.0307), a higher manual mCBV (P = 0.018) and a higher semiautomatic mCBV (P = 0.0111) than that of the PCNSL. Semiautomatic mCBV had the highest value (0.815) for the area under the curve (AUC), however, the AUCs of the three parameters were not significantly different from each other. The semiautomatic mCBV was the best independent predictor for the GBM and PCNSL differential diagnosis according to the stepwise multiple regression analysis. Conclusion: We found that the semiautomatic mCBV could be a better predictor than the manual mCBV for the GBM and PCNSL differentiation. We believe that the semiautomatic segmentation method can contribute to the advancement of perfusion based brain tumor evaluation.

• Journal of the Korean Society of Radiology
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• v.6 no.6
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• pp.507-513
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• 2012

This research was performed to evaluate the superparamagnetic iron oxide nanoparticles'(SPIONs) cell toxicity and to measure the radiation cell survival curve changes of SPIONs-uptake glioblastoma multiforme cells. The results could be practically used as the fundamental data to ameliorate proton beam cancer therapy, for example, providing necessary GBM treatment dose in the proton beam therapy when the therapy takes advantage of SPIONs. The assessment of the toxicological evaluation of synthesized SPIONs was accomplished by MTT assay as an in vitro experiment. The results showed no meaningful differences in the cell survival rate at the $1-100{\mu}g/ml$ SPIONs concentrations, but the cell toxicity was shown as the cell survival rate decreased up to 74.2% at the $200{\mu}g/ml$ SPIONs concentration. Then, we measured each radiation cell survival curve for U373MG cells and SPIONs-uptake U373MG cells with 0~5 Gy of proton beam irradiations. It is learned from the analysis of the experimental results that the SPION-uptake cells' radiation survival rate was more rapidly decreased as the irradiation dose increased. In conclusion we confirmed that SPIONs-uptake in U373MG cells induces cell death at the much less dose than the lethal dose of SPION-non-uptake cell. This research shows that the therapeutic efficacy of glioblastoma multiforme treatment in proton beam therapy can be improved by SPIONs targeting to the GBM cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.6
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• pp.2793-2796
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• 2014

Background: Glioblastoma multiform (GBM) is a highly aggressive tumor with median survival of approximately 14 months. Management consists of maximal surgical resection followed by post-operative chemoradiation with concurrent then adjuvant temozolamide. The standard radiotherapy dose is 60Gy in 2-Gy fractions recommended by the radiation therapy oncology group (RTOG). With the vast majority of tumor recurrences occurring within the previous irradiation field and the poor outcome associated with standard therapy, regimens designed to deliver higher radiation doses to improve local control and enhance survival are needed. In this study, we report a single institutional experience in treatment of 68 consecutive patients with GBM, treated with resection, and given post-operative radiotherapy followed by concurrent and/or adjuvant chemotherapy. Results: Of the 80 patients who entered this study, 68 completed the treatment course; 45 (66.2%) males and 23 (33.8%) females with a mean age at diagnosis of $49.0{\pm}12.9$ (21-75) years. At a median follow up of 19 months, 39 (57.3%) patients had evidence of tumor progression and 36 (52.9%) had died. The median over all survival for all patients was 16 months and progression free survival for all patients was 6.02 months. All potential prognostic factors were analyzed to evaluate their effects on overall survival. Age ${\leq}50$ year, concurrent and adjuvant chemotherapy and extent of surgery had significant p values. We found lower progression rate among patients who received higher doses of radiotherapy (>60Gy). Higher radiation doses improved progression free survival (p=0.03). Despite increasing overall survival, this elevation was not significant. Conclusions: This study emphasize that higher radiation doses of (>60Gy) can improve local control and potentially survival, so we strongly advise prospective multi centric studies to evaluate the role of higher doses of radiotherapy on GBM patient outcome.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.9
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• pp.4205-4208
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• 2016

Background: The aim of this study was to analyse the expression of EGFR in newly diagnosed and recurrent glioblastoma multiforme (GBM). Materials and Methods: Our study included a total of 48 paired samples collected from 24 patients diagnosed with GBM. The intensity of EGFR cytoplasmatic staining was scored on a scale of 1-3+ (weak, intermediate or strong). Results: We found EGFR overexpression in 23 patients (96%) with newly diagnosed GBM, while all recurrent tumours overexpressed EGFR. Ten recurrent tumours (42%) had a lower expression than their new counterpart 13 tumours (54%) had a similar expression, and only one case (2%) had increased expression on recurrence. The expression of EGFR in newly diagnosed GBM was significantly correlated with EGFR expression in recurrent tumour (p = 0.036). In addition, new GBMs with strong EGFR expression had a mean relapse-free interval of 11.5 months (p=0.017). A benefit of combined therapy was observed in the radiotherapy-plus-chemotherapy group where the average time was 11 months (p=0.011), as compared with surgery/radiotherapy alone (average time 6.8 months). Conclusions: The present data show that EGFR is overexpressed in paired GBMs. The discrepancies of EGFR expression between the primary tumour and the recurrence suggest heterogeneity of GBMs but also unity at relapse.

• Molecules and Cells
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• v.37 no.7
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• pp.547-553
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• 2014

Glioblastoma multiforme (GBM) is one of the most common brain malignancies and has a very poor prognosis. Recent evidence suggests that the presence of cancer stem cells (CSC) in GBM and the rare CSC subpopulation that is resistant to chemotherapy may be responsible for the treatment failure and unfavorable prognosis of GBM. A garlic-derived compound, Z-ajoene, has shown a range of biological activities, including anti-proliferative effects on several cancers. Here, we demonstrated for the first time that Z-ajoene specifically inhibits the growth of the GBM CSC population. CSC sphere-forming inhibition was achieved at a concentration that did not exhibit a cytotoxic effect in regular cell culture conditions. The specificity of this inhibitory effect on the CSC population was confirmed by detecting CSC cell surface marker CD133 expression and biochemical marker ALDH activity. In addition, stem cell-related mRNA profiling and real-time PCR revealed the differential expression of CSC-specific genes, including Notch, Wnt, and Hedgehog, upon treatment with Z-ajoene. A proteomic approach, i.e., reverse-phase protein array (RPPA) and Western blot analysis, showed decreased SMAD4, p-AKT, 14.3.3 and FOXO3A expression. The protein interaction map (http://string-db.org/) of the identified molecules suggested that the AKT, ERK/p38 and $TGF{\beta}$ signaling pathways are key mediators of Z-ajoene's action, which affects the transcriptional network that includes FOXO3A. These biological and bioinformatic analyses collectively demonstrate that Z-ajoene is a potential candidate for the treatment of GBM by specifically targeting GBM CSCs. We also show how this systemic approach strengthens the identification of new therapeutic agents that target CSCs.

• Journal of Life Science
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• v.29 no.5
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• pp.530-536
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• 2019

Glioblastoma (GBM) is the most incurable brain cancer derived from the transformed glial cells. Standard anti-GBM treatment, including surgery and chemoradiotherapy, does not ensure good prognosis for the patients with GBM, because successful therapy is often impeded by presence of glioma stem cells (GSCs). GSCs, which is generally divided into proneural (PN) and mesenchymal (MES) subtype, are understood as subpopulation of cancer cells responsible for GBM initiation, progression and recurrence after standard treatments. In the present study, we demonstrate that PN subtype GSCs differentially transit to MES subtype GSCs by specific cytokines. The expression of CD44, a marker of MES subtype GSCs, was observed when GSC11 PN subtype GSCs were exposed to tumor necrosis factor alpha ($TNF-{\alpha}$) cytokine and GSC23 PN subtype GSCs were treated to transforming growth factor beta 1 ($TGF-{\beta}1$) cytokine. Ivy glioblastoma atlas project (Ivy GAP) bioinformatics database showed that $TNF-{\alpha}$ and $TGF-{\beta}1$ were highly expressed in necrotic region and perivascular region, respectively. In addition, $TNF-{\alpha}$ signaling was relatively upregulated in necrotic region, while $TGF-{\beta}$ signaling was increased in perivascular region. Taken together, our observations suggest that MES subtype GSCs can be derived from various PN subtype GSCs by multimodal cytokine stimuli provided by neighboring tumor microenvironment.

• Korean Journal of Radiology
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• v.22 no.8
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• pp.1369-1378
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• 2021

Objective: Few attempts have been made to investigate the prognostic value of dynamic contrast-enhanced (DCE) MRI or dynamic susceptibility contrast (DSC) MRI of non-enhancing, T2-high-signal-intensity (T2-HSI) lesions of glioblastoma multiforme (GBM) in newly diagnosed patients. This study aimed to investigate the prognostic values of DCE MRI and DSC MRI parameters from non-enhancing, T2-HSI lesions of GBM. Materials and Methods: A total of 76 patients with GBM who underwent preoperative DCE MRI and DSC MRI and standard treatment were retrospectively included. Six months after surgery, the patients were categorized into early progression (n = 15) and non-early progression (n = 61) groups. We extracted and analyzed the permeability and perfusion parameters of both modalities for the non-enhancing, T2-HSI lesions of the tumors. The optimal percentiles of the respective parameters obtained from cumulative histograms were determined using receiver operating characteristic (ROC) curve and univariable Cox regression analyses. The results were compared using multivariable Cox proportional hazards regression analysis of progression-free survival. Results: The 95th percentile value (PV) of Ktrans, mean Ktrans, and median Ve were significant predictors of early progression as identified by the ROC curve analysis (area under the ROC curve [AUC] = 0.704, p = 0.005; AUC = 0.684, p = 0.021; and AUC = 0.670, p = 0.0325, respectively). Univariable Cox regression analysis of the above three parametric values showed that the 95th PV of Ktrans and the mean Ktrans were significant predictors of early progression (hazard ratio [HR] = 1.06, p = 0.009; HR = 1.25, p = 0.017, respectively). Multivariable Cox regression analysis, which also incorporated clinical parameters, revealed that the 95th PV of Ktrans was the sole significant independent predictor of early progression (HR = 1.062, p < 0.009). Conclusion: The 95th PV of Ktrans from the non-enhancing, T2-HSI lesions of GBM is a potential prognostic marker for disease progression.